The proposed investigations on Hageman factor (human coagulation Factor XII) and on the Hageman factor pathways are designed to provide fundamental biochemical and physico-chemical knowledge about the activation and control of the components of the Hageman factor pathways. These pathways include: the intrinsic clotting system, the kallikrein-kinin system, and the plasmin-fibrinolytic system. Detailed knowledge about the molecular mechanisms of activation and enzymatic specificity of Hageman factor and its substrate proteins (kallikrein, Factor XI, and plasminogen proactivator) is essential to the long range goal of a thorough evaluation of the contributions of the Hageman factor pathways to the pathogenesis of disease. A major long term goal of this proposal is to assess critically the participation and fate of each clotting factor of the intrinsic pathway in plasma during the coagulation process. This project will involve extensive studies of radiolabeled-purified clotting factors which are added back to plasma. These experiments will provide direct information about the mechanisms of proteolytic activation and inhibition of each clotting factor in clotting plasma. A further objective of these studies is the synthesis of oligopeptide activators, inhibitors, and substrates of Hageman factor and kallikrein. Such synthetic peptides might prove to be fibrinolytic agents or anticoagulants, while the substrates may serve as convenient reagents for in vitro assays of these enzymes.